1-(3-hydroxy-4-methyl-phenyl)-propylamine (-2) and the salts thereof

ABSTRACT

COMPOUNDS REPRESENTED BY THE FORMULA   1-(H2N-CH(-R1)-H2C-),3-HO,R2-BENZENE   WHEREIN R1 IS A MEMBER OF THE GROUP CONSISTING OF CH3, C2H5 AND C3H7, AND R2 IN POSITION 2, 4, 5 OR 6 ON THE BENZENE NUCLEUS IS A MEMBER OF THE GROUP CONSISTING OF F, CL, BR, CH3, C2H5 AND C3H7, PHARMACEUTICAL COMPOSITIONS CONTAINING THESE COMPOUNDS, AND THE USE THEREOF FOR THERAPEUTIC PURPOSES.

United States Patent 1-(3-HYDROXY-4-METHYL-PHENYL)-PROPYL- AMINE (-2)AND THE SALTS THEREOF Per Arvid Emil Carlsson, Goteborg, Hans RudolfCorrodi,

Askim, Sven Giiran Hallhagen, Molndal, and Ulf Krister Junggren,Goteborg, Sweden, assignors to Aktiebolaget Hassle, Goteborg, Sweden NoDrawing. Filed Mar. 28, 1969, Ser. No. 811,662 Claims priority,application Sweden, Apr. 1, 1968,

Int. Cl. C07c 87/28 US. Cl. 260-50117 2 Claims ABSTRACT OF THEDISCLOSURE Compounds represented by the formula NHz CH2(|3H wherein R isa member of the group consisting of CH C H and C3H7, and R in position2, 4, 5 or 6 on the benzene nucleus is a member of the group consistingof F, Cl, Br, CH C H and C H pharmaceutical compositions containingthese compounds, and the use thereof for therapeutic purposes.

R wherein R is a member of the group consisting of CH;,, C H and C3H7,and R in position 2, 4, 5 or 6 on the benzene nucleus, is a member ofthe group consisting of F, Cl, BI, CH3, C2H5 and Cal I7- Prior artcompounds are 3-hydroxy-4-methyl-norephedrine;

v HOCHCH OH; (H)

"Ice

and a-methyl-m-tyraminez NHz 0min: 2111.

(III) The compounds of this invention have been shown to possessantihypertensive and antidepressant properties without giving rise toundesired sympathomimetie side effects. Surprisingly it has been foundthat the compounds of the invention are able to penetrate into thebrain, where they are taken up by the noradrenergic neutrons and actthere as false transmitters. This valuable and unexpected propertycontributes to the antihypertensive and antidepressant activity of thecompounds.

The prior art compound II has no antihypertensive and antidepressantelfects, since it does not penetrate into the brain and displacenoradrenaline there.

The prior art compound III does penetrate the blood brain barrier, butshows a high sympathomimetic activity which leads to an increase inblood pressure. The increase in blood pressure caused by this sideeffect overshadows the antihypertensive etfect which might be expectedfrom the ability of the compound to act as a false transmitter in thenoradrenergic neurons of the brain. Furthermore, the compound III ismore toxic than the compounds disclosed in this invention.

An additional advantage of the compounds of this invention over thementioned prior art compounds is that the substances disclosed hereinare able to liberate 5-hydroxytryptamine in the brain. This propertycontributes mainly to the antidepressant activity of the compounds. Noneof the mentioned prior art compounds shows this etfect.

The compounds of the invention may be prepared by known methods such as(A) Replacing Z with H in a compound of the formula NH: CH2|CH R (II)wherein R and R have the meanings specified above and wherein Z is amember of the group consisting of alkyl and acyl protecting groups, bymeans of a strong acid such as HBr to the formation of a compound of theFormula I;

(B) Replacing Z with H by catalytical hydrogenation of a compound of theformula 7 (iJHzCH R (III) wherein R has the meaning specified above; Ris a member of the group consisting of ---CH,, C H and C H and wherein Zis a member of the group consisting of aralkyl protecting groups, suchas benzyl; to the formation of a compound of the Formula I;

() Reducing a compound of the formula CHzC 0 R (IV) wherein R and K havethe meanings specified above, in

the presence of HCOOH according to Leuckart to the formation of acompound of the Formula I; (D) Reducing a compound of the formula wHOCHCH wherein R has the meaning specified above and wherein R is amember of the group consisting of CH C H and C H to the formation of acompound of the Formula I;

(E) Reducing a compound of the formula wherein R and R have the meaningsspecified above, to the formation of a compound of the Formula I;whereafter the compound of the Formula I thus obtained if necessary istransformed into a therapeutically acceptable salt by reaction with theappropriate acid.

Z is preferably a methyl group, and Z is preferably a benzyl group.

Z may be split oif by strong acids such as HBr, and Z may be split offby hydrogenolysis.

The reaction way D is applicable only in those cases when thesubstituent R in the compound of the Formula I is -CH -C H or C3H7.Catalytical removal of araliphatic protecting groups is not applicablewhen the substituent R is F, C1 or Br. When R is CH -C H or -C H all theoutlined reaction ways can be used, and catalytical removal of anaraliphatic protecting group is possible.

The reduction of the compound of the Formula V is preferably carried outby catalytical hydrogenation.

The reduction of the compound of the Formula VI is preferably carriedout by means of a complex metal hydride such as lithium aluminiumhydride.

Starting materials for the processes described above may be prepared inany desired way. Some of the possible ways for preparation of startingmaterials used in the methods A, B, C and E above are outlined in thefollowing reaction schemes, which also serve as further illustrations ofthe various methods of preparation as described above. The substituentsR R R used in the reaction formulas have the meanings given above, Z ishydrogen or the radical Z and Z is hydrogen or the radical Z Startingmaterials for the reaction Way D may be prepared by methods well knownper se.

4 Method A:

CHO CH=CNO2 RCHaNOz LlAlH4 CHZCHNHQ CH1 E HBr OZ OH Method B:

CHO CH=CNO RCHzNOz Fe HCl Q-OZ -OZ Ra 33 NH: NH: (3112310 $112+H 1112 IH 1100011 (Leuckart;

reaction) 112/ P d LD-oz HCONHZ 0z -o1-r R R3 R3 Method C:

CHO CH=CNO2 l l Q R cHrNoz Fe HCl 0Z OZ NH2 $11260 (ilHfll o CH2 I H Q Qnooon (Leuckart HBr reaction) v -oz OH HCONHI -on Method E:

NH: CH=CNO CHZH I l R1 LlA1H4 -OH -OH The compounds of the inventionexist in the form of optically active isomers, which may be isolated inany principally known way for resolution of an amine, and it isunderstood that such a manner will be included within the scope of thisinvention.

The racernate obtained at the above reactions can be resolved into theenantiomers 'by converting the free base into a salt or an amide of anoptically active acid such as tartaric acid or any other opticallyactive acid capable of forming crystalline salts with the amine, andregeneration of the amine after the usual separation of thediastereomeric mixture thus obtained.

It will also be understood that the compounds of the present inventionmay be used either as a purified isomer which is biologically active orin the form of the mixed isomeric product obtained as a naturalconsequence of the reaction sequences described above, or any otherreaction sequence for the preparation of the compounds which results ina mixed isomeric product containing the biologically active isomer orisomers.

The new compounds according to the invention may be administered in theform of salts with physiologically acceptable acids. Suitable acidswhich may be used are, for example, hydrochloric, hydrobromic,sulphuric, fumaric, citric, tartaric, maleic or succinic acid.

The invention further provides pharmaceutical compositions comprising asactive ingredient at least one of the compounds according to theinvention in association with a pharmaceutical carrier. Suchcompositions may be designed for oral, rectal or parenteraladministration.

To produce pharmaceutical preparations in the form of dosage unit fororal application containing a compound of the invention in the form ofthe free base, or a pharmaceutically acceptable salt thereof, the activeingredient may be mixed with a solid, pulverized carrier, for examplelactose, saccharose, sorbitol, mannitol, a starch such as potato starch,corn starch, maize starch or amylopectin, a cellulose derivative ofgelatin, and also may include lubricants such as magnesium or calciumstearate or a C-arbowax or other polyethylene glycol waxes andcompressed to form tablets or centres for drages. If drages arerequired, the centres may be coated, for example with concentrated sugarsolutions which may contain gum arabic, talc and/or titanium dioxide, oralternatively with a lacquer dissolved in easily volatile organicsolvents or mixtures of organic solvents. Dyestuffs can be added tothese coatings. For the preparation of soft gelatin capsules(pearl-shaped closed capsules) consisting of gelatin and, for example,glycerol, or similar closed capsules, the active substance may beadmixed with a Carbowax. Hard gelatin capsules may contain granulates ofthe active substance with solid, pulverized carriers such as lactose,saccharose, sorbitol, mannitol, starches (for example potato starch,corn starch or amylopectin), cellulose derivatives or gelatin, and mayalso include magnesium stearate or stearic acid. Dosage units for rectalapplication may be in the form of suppositories comprising the activesubstance in admixture with a neutral fatty base, or gelatin rectalcapsules comprising the active substance in admixture with a Carbowax orother polyethylene glycol waxes. Each dosage unit preferably contains 1to 200 mg. of active ingredient.

Liquid preparations for oral application may be in the form of syrups,suspensions or emulsions, for example containing from about 0.1% to 20%by weight of active substance and also, if desired, such adj'uvants asstabilizing agents, suspending agents, dispersing agents, flavouringagents and/ or sweetening agents.

Liquid preparations for rectal administration may be in the form ofaqueous solutions containing from about 0.1 to 2% by weight of activesubstance and also, if desired, stabilizing agents and/ or buffersubstances.

For parenteral application by injection the carrier may be a sterile,parenterally acceptable liquid e.g. pyrogenfree water or an aqueoussolution of polyvinylpyrrolidone, or a parenterally acceptable oil, e.g.arachis oil, and optionally stabilizing agents and/or buffer substances.Dosage units of the solution may advantageously be enclosed in ampoules.

When given by oral or rectal administration, the compounds of theinvention such as l-(m-hydroxy-p-methylphenyl)-butylamine (-2) and1-(In-hydroxy)-p-methylphenyl-propylamine (-2), may be given in widelyvarying dosages from, for example, 20 mg./day to 1 g./ day, but dosage-sof 50500 mg./day will ordinarily be given, amounts between 100 and 300mg./day being usually preferred. When given by i.v. administration,dosages of about 5-100 mg./day, preferably about -50 mg./day may beused.

The invention is further illustrated by the following examples.

Example I.Preparation of starting material (a) Preparation ofl-(m-methoxy-p-methyl-phenyl)-2- nitro-l-propene TABLE 1 M.P., Z C.

CH3 51 CH3 CH 48 CO CH3 47 CH3 76 CH3 65 CH3 80 CH; 88

(b) Preparation of m-methoxy-p-methyl-phenylacetone To a solution of 0.8mole of 1-(m-methoxy-p-methyl phenyl)-2-nitro-1-propene in 300 m1. oftoluene and 875 m1. of water was added 326 g. of iron powder and 3.3 g.of ferric chloride hexahydrate. The mixture was stirred and heated to 80C. 292 m1. of cone. hydrochloric acid was added at such a rate thatreflux was maintained. After addition of the hydrochloric acid, themixture was stirred and refluxed for /2 hour, and thereaftersteam-distilled. The distillate was extracted with ether, and theorganic layer washed twice With a 3 percent sodium bisulphite solution,then water, dried over anhydrous magnesium sulphate and evaporated. Theremainder was pure enough for the next step.

(c) Preparation of 1-(m-methoxy-p-methyl-phenyl)- propylamine (-2) 0.044mole of the substituted 2-phenylpropanone, 13.5 g. of freshly distilledformamide and 2.5 g. of formic acid was refluxed with stirring during 5hours. After cooling 50 ml. of water and 50 ml. of hydrochloric acid wasadded and the mixture refluxed for 5 hours. After alkalisation with 30%NaOH the product was taken up in either. The organic layer was dried andevaporated.

(d) Preparation of l-(m-methoxy-p-methylphenyl)- propylamine-2 67.1 g.of 1-(m-methoxy-p-methylphenyl)-2-nitro-1- propene in 200 ml. of dryether was added to a stirred mixture of 32 g. of LiAlH in 1000 ml. ofdry ether at such a rate that the solvent refluxed gently withoutexternal heating. The mixture was stirred and heated for two hours. 20ml. of ethyl-acetate was then added carefully w th vigorous stirring,followed by 40 ml. of water. The mixture was filtered and the etherealsolution was shaken with 2-N hydrochloric acid. The amine was obtainedupon alkalisation of the acidic solution and ether extraction. Theproduct could be used without further purification in the subsequentstep. The compounds specified in Table 2 were prepared by the samemethod. R and R have the significance given above, and Z is used todesignate the protecting group used.

7 EXAMPLE 2 Preparation of 1-(m-hydroxy-p-methylphenyl)- propylamine-2(a) 39.3 g. of 1-(m-methoxy-p-methylphenyl)-propylamine-(2) in 300 ml.of concentrated hydrobromic acid (d.=1.49) was refluxed for 3 hours. Thesolution was then evaporated to dryness and dissolved in water. TheWater solution was made slightly alkaline with ammonia and theprecipitate recrystallized from di-isopropyl-ether.

In an analogous way the following substances were prepared. R and R havethe significance given above.

TABLE 3 (b) 1.81 g. of m-hydroxy-p-methyl-norephedrine was dissolved in20 ml. of 1 N hydrochloric acid and hydrogenated with Pd/C as catalystat 50. After 5 hours 250 ml. of H had been taken up and the desoxybasewas isolated by alkalisation of the filtered solution. Afterrecrystallization from di-isopropylether the melting point was found tobe 134 C. The substance was identical with the one obtained in Example2a.

EXAMPLE 3 Preparation of 1-(rn-hydroxy-p-ethyl-phenyl)- propylamine (-2)1-(rn-hydroxy-p-ethyl-phenyl)-propylamine (-2) was prepared by reductionof 1-(m-hydroxy-p-ethyl-phenyl)- 2-nitro-l-propene by means of LiAlH bythe same method as in Example 1d. M.P.: 109 C.

The following examples illustrate how the compounds of the instantinvention can be incorporated in pharmaceutical compositions.

EXAMPLE 4.--TABLETS Each tablet contains:

Mg. Active substance 50.0 Maize starch 25.0 Lactose 160.0 Gelatin 1.5Talc 12.0

Magnesium stearate 1.5

250.0 EXAMPLE 5.-SUPPOSITORIES Each suppository contains:

8 EXAMPLE 7.-INJECTION SOLUTION Mg. Active substance 0.100 Sodiumpyrosulfite 0.500 Disodium edetate 0.100 Sodium chloride 8.500 Sterilewater for injection ad 1.00

EXAMPLE 8.SOLUTION FOR RECTAL ADMINISTRATION (RECTAL VIALS) Activesubstance20.0 mg. Sodium pyrosulfite-LS mg. Disodium edetate0.3 mg.Sterile water-ad 3.0 ml.

EXAMPLE 9.DROPS Active substance2.00 g. Ascorbic acid-1.00 g. Sodiumpyrosulfite0.l0 g. Disodium edetate-0.l0 g. Liquid glucose50.00 g.Absolute alcohol10.00 g. Purified water-ad 100.0 ml.

EXAMPLE 10.TABLETS Active substance g.), lactose g.), calcium citrate(50 g.), and starch (50 g.) are mixed together and granulated using a10% aqueous gelatin solution. The granules are passed through a ZO-meshsieve, mixed with magnesium stearate (1.5 g.) and tale (5 g.), and thentabletted using a 9 mm. punch.

PHARMACOLOGICAL TESTS (I) Effect as releasers and displacers ofnoradrenaline in the mouse brain The substances were givenintraperitoneally to mice (male, NMRI, b.w. of 18-22 g.) in a dosage of30 mg./kg. 6 animals per group were used. The noradrenaline in thebrains was determined fluorometrically according to Bertler, Carlssonand Rosengren, Acta. physiol. scand. 44, 273 (1958) 1, 2, 4 and 8 hoursafter the administration. The values are given in percents of normalvalues (450 :9 ng./g.).

TABLE 4 Sympath- Amount of noradrenaline in omimetie the brain. Percentof normal effect;

values after- (piloerection.

salivation, R R 1 hr. 2 hrs. 4 hrs. 8 hrs. exophthalmos) This testshows:

(a) That the prior art compound II, 3-hydroxy-4- methyl-norephedrine,does not penetrate into the brain and displace noradrenaline, whichwould result in a decrease of noradrenaline in the brain,

(b) That the prior art compound III, u-methyl-m-tyramine, has anunwanted high sympathomimetic effect leading to excessive signs ofpiloerection, salivation, exophthalmos.

(c) That the substances disclosed in this invention penetrate into thebrain and cause release of noradrenaline through displacement (expressedas a decrease in noradrenaline) without causing disturbingsympathomimetic effects.

9 (II) Toxicity The intraperitoneal and the peroral toxicity wasdetermined as LD in mice.

This test shows that the compounds disclosed in this invention have alow intraperitoneal and oral toxicity compared with the prior artcompounds 11 and III.

(III) Antihypertensive effect When 1(m-hydroxy-p-methylphenyl)-propylamine-2 was given as a solution in thedrinking water to renally hypertensive rats in doses of 5-10 mg./kg./daytheir blood pressure (170-200 mm. Hg) decreased to 100-120 mm. Hg in afew days and remained there until the administration of the drug wasstopped. The prior art compounds II and III did not react similarly whenadministered in the same dosage; compound II does not lower bloodpressure and compound III causes an initial increase in blood pressureto 190-210 mm. Hg due to its sympathomimetic efi'ect, whereafter theblood pressure decreases moderately.

This test shows that only compounds which penetrate into the brain andcause liberation and displacement of noradrenaline there haveantihypertensive activity. The prior art compound III has anantihypertensive action which is masked by the sympathomimetic action ofthe substance leading to an initial undesirable increase in bloodpressure.

(IV) Efiect as releasers and displacers of 5- hydroxytryptamine in themouse brain Substances according to the invention were givenintraperitoneally to mice (male, NMRI, b.w. 18-22 g., 6 animals/ group).The amount of S-hydroxytryptamine in the brain was determinedfluorimetrically according to Bertler and Rosengren, Experientia 15 382(1959), 4 hours after the administration.

The values are given in percents of normal values (460:14 ng/g).

TABLE 6 Amount of fi-hydroxytryptamine after 4 hours, percent of nor-Dose, mgJkg. mal values This test shows that the compounds disclosed inthe invention are able to liberate and displace S-hydroxytryptamine inthe mouse brain, in contrast to the related prior art compound III,u-methyl-m-tyramine. Higher doses than 50 mg./kg. could not be used forthe prior art compounds II and III due to the toxicity of thesecompounds.

What is claimed is:

1. 1 (3 hydroxy 4-methyl-phenyl)-propylamine (-2) and therapeuticallyacceptable salts thereof.

2. A compound according claim 1 in form of their optical antipodes, or atherapeutically acceptable salt thereof.

References Cited UNITED STATES PATENTS 2,146,476 2/1939 Hildebrandt etal. 260-5708 3,187,046 6/ 1965 Curtis 260570.8 3,188,349 6/1965 Krohs etal. 260570.=8 3,198,833 8/1965 Beregi et al. 2-60570.8

OTHER REFERENCES Wenner, Chemical Abtracts, Vol. 46, pages 1487-88ROBERT V. HINES, Primary Examiner U.S. Cl. X.R.

@2 3 UNITED STATES PATENT OFFICE @ERTIFCTE F QRREC@N Patent No. ,737Dated April 1972 Inventor-( Per CarlSSOn et 3.1.

It is certified that error appears in the above-identified patent andthat said Letters Patent are hereby corrected as shown below:

Col. 2, line 14, "neutrons should be -neuron's;

Col. 5, 7

line 53, "0.1" should be 0.l%;

Col. 6, line 2, "ofl" should be of l-;

line 22 of Table l, "4C H should be 4-C H Col. 7, line 7, "(d.=1.49)"should be -(d=l.49);

Col. 10, line 9, after "hours" should be line 17, "191.1" should bev--1l9.l--;. line 19, "the" second occurrence" should be --this-.

Signed and sealed this 26th day of September 1972.

(SEAL) Attest:

EDWARD M.FLETCHER,JR, ROBERT GOTTSCHALK Attesting Officer Commissionerof Patents AUliU H050 UNITED STATES PATENT OFFICE CERTIFICATE OFCORRECTION Petent No. 3r655r737 Dated April 1972 lnventoifls) Per ArvidEmil Carlsson et al It is certified that error appears in theabove-identified patent and that said Letters Patent are herebycorrected as shown below:

Col. 2, line 14, "neutrons should be neurons--;

line 53, "0.1" should be -O.l%--;

Col. 6, line 2, 'ofl" should be .of l;

line 22 of Table l, "4C=H should be -4C H Col. 7, line 7, (d.=l.49)should be (d=l.49)-;

Col. 10, line 9, after "hours" should be line 17, "191.1" should be--ll9 .l-; line 19, "the" second occurrence" should be -this-.

Signed and sealed this 26th day of September 1972 (SEAL) Attest:

EDWARD M.FI.ETCHER, JR. ROBERT GOTTSCHALK Attesting Officer Commissionerof Patents

